Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
refractory anemia with excess blasts in transformation, refractory anemia with excess blasts, chronic myelomonocytic leukemia, secondary acute myeloid leukemia, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, de novo myelodysplastic syndromes
Brief summary
RATIONALE: Drugs used in chemotherapy, such as arsenic trioxide and gemtuzumab ozogamicin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving arsenic trioxide together with gemtuzumab ozogamicin works in treating patients with advanced myelodysplastic syndromes.
Detailed description
OBJECTIVES: Primary * Determine the efficacy of arsenic trioxide and gemtuzumab ozogamicin to achieve complete and partial remissions in patients with advanced myelodysplastic syndromes. Secondary * Determine the efficacy of this regimen, in terms of 50% decrease in Red Blood Cell (RBC) transfusion requirements and change in hemoglobin concentration from baseline in patients treated with this regimen. * Determine the platelet, neutrophil, bone marrow, and cytogenic response in patients treated with this regimen. * Determine the response duration in patients treated with this regimen. * Determine the quality of life of patients treated with this regimen. * Determine the safety and toxicity of this regimen in these patients. OUTLINE: This is a multicenter, open-label study. Patients receive arsenic trioxide IV over 1 hour once daily on days 1-5 in week 1 and then twice weekly in weeks 2-12. They also receive gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 12 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline, every 12 weeks during study treatment, and then 4 weeks after the completion of study treatment. After completion of study treatment, patients are followed periodically. PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.
Interventions
DRUGarsenic trioxide
Arsenic trioxide will be administered at a dose of 0.25 mg/kg/day IV over 1-2 hours for 5 consecutive days during the first week. Subsequently, arsenic trioxide will be given at a dose of 0.25mg/kg/day twice a week for 11 additional weeks (weeks 2-12).
DRUGgemtuzumab ozogamicin
Gemtuzumab ozogamicin consists of a 2 hr infusion at a dose of 3mg/m2 on day 8 of each 12-week cycle. Gemtuzumab ozogamicin should be administered at a minimum of one hour after the completion of the arsenic trioxide infusion
Sponsors
University of Michigan
National Cancer Institute (NCI)
The Cleveland Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of one of the following hematologic malignancies: * Myelodysplastic syndromes (MDS) of one of the following French-American-British (FAB) classifications: * Refractory anemia with excess blasts (RAEB) (WHO RAEB-1) * RAEB in transformation (RAEB-t) (RAEB-2) * Chronic myelomonocytic leukemia (CMML) with \> 5% myeloblasts (WHO CMML-2) * International Prognostic Scoring System (IPSS) score of intermediate-2 or higher in the setting of \> 5% myeloblasts * Acute myeloid leukemia that has evolved from MDS * Must not be a candidate for bone marrow transplantation as first-line therapy or must have declined bone marrow transplantation PATIENT CHARACTERISTICS: * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 * Life expectancy of at least 4 months * Serum potassium ≥ 4.0 milliequivalent (mEq/dL) and serum magnesium ≥ 1.8 mg/dL (supplemental electrolytes allowed) * Absolute corrected QT interval (QTc) interval \< 460 msec * No serious medical condition, laboratory abnormality, or psychiatric illness that, in the view of the treating physician, would place the patient at an unacceptable risk if he or she were to participate in the study or would prevent that person from giving informed consent * Not pregnant or nursing * Fertile patients must be willing to use adequate contraception (barrier method with spermicidal jelly, intrauterine device (IUD), or oral contraceptives) * Negative pregnancy test * Creatinine \> 2.5 mg/dL * serum glutamate oxaloacetate transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) \> 1.5 times upper limit of normal * Bilirubin \> 2.0 mg/dL * No history of malignancy within the past 3 years other than MDS except basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast * Arsenic trioxide is contraindicated in patients who are hypersensitive to arsenic PRIOR CONCURRENT THERAPY: * No prior bone marrow transplantation * Must not receive another investigational or approved therapy for MDS within 4 weeks of study enrollment, including growth factors (within 1 week of study enrollment) * No prior arsenic trioxide or gemtuzumab ozogamicin * No other concurrent cytotoxic drugs or investigational agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete and Partial Remission Per the International Working Group (IWG) Criteria for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML) | at 12 weeks post treatment | The null hypothesis to be tested was the percentage who will respond to combination arsenic trioxide (ATO) and gemtuzumab ozogamicin (GO) therapy is \<10%. A total of \>/= 9 responses observed in 30 evaluable patients was taken as evidence warranting further study of the regimen, provided the toxicity profile also appears favorable. The IWG Criteria standardizes the clinical responses in MDS and AML based upon hematologic improvement, quality of life and cytogenic improvement. These standardizations allow for the responses to be determined as either complete responses or partial responses. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From date of enrollment to a minimum of three years for survival | Patient's Overall Survival from date of enrollment to a minimum of three years for survival. |
| Tolerability | 12 Weeks | Tolerability of Therapy was assessed through use of the National Cancer Institute Common Toxicity Criteria (version 3.0). Treatment tolerability was determined based upon whether or not the physician determined therapy was in the patient's best interest, whether the patient wanted to continue therapy or not, whether patients discontinued treatment due to progressive disease, or whether patients discontinued treatment due to toxicity. |
Countries
United States
Participant flow
Recruitment details
Patients were enrolled at Cleveland Clinic and the University of Michigan from February 2004 through June 2006.
Participants by arm
| Arm | Count |
|---|---|
| ATO (0.25mg/kg) and GO (3mg/m2) ATO dosing was based on the phase 2 European Union regimen at a dose of 0.25 mg/kg administered intravenously on Days 1 through 5 during Week 1 and then twice weekly during Weeks 2 to 12, and GO at a dose of 3mg/m2 on Day 8 for 1 or 2 cycles of 12 weeks each. | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | ATO (0.25mg/kg) and GO (3mg/m2) |
|---|---|
| Age, Continuous | 69 years |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 28 / 30 |
| serious Total, serious adverse events | 19 / 30 |
Outcome results
Primary
Complete and Partial Remission Per the International Working Group (IWG) Criteria for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML)
The null hypothesis to be tested was the percentage who will respond to combination arsenic trioxide (ATO) and gemtuzumab ozogamicin (GO) therapy is \<10%. A total of \>/= 9 responses observed in 30 evaluable patients was taken as evidence warranting further study of the regimen, provided the toxicity profile also appears favorable. The IWG Criteria standardizes the clinical responses in MDS and AML based upon hematologic improvement, quality of life and cytogenic improvement. These standardizations allow for the responses to be determined as either complete responses or partial responses.
Time frame: at 12 weeks post treatment
Population: Responses According to IWG MDS Criteria (n=30) Responses According to IWG AML Criteria (n=12)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATO + GO | Complete and Partial Remission Per the International Working Group (IWG) Criteria for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML) | Responses according to IWG MDS Criteria | 30 percentage of patients |
| ATO + GO | Complete and Partial Remission Per the International Working Group (IWG) Criteria for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML) | Responses according to IWG AML Criteria | 25 percentage of patients |
| ATO + GO | Complete and Partial Remission Per the International Working Group (IWG) Criteria for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML) | Responses according to Both Criteria | 10 percentage of patients |
Secondary
Overall Survival
Patient's Overall Survival from date of enrollment to a minimum of three years for survival.
Time frame: From date of enrollment to a minimum of three years for survival
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ATO + GO | Overall Survival | Overall Survival | 9.7 months |
| ATO + GO | Overall Survival | Responders Overall Survival | 28.6 months |
| ATO + GO | Overall Survival | Nonresponders Overall Survival | 7.6 months |
Secondary
Tolerability
Tolerability of Therapy was assessed through use of the National Cancer Institute Common Toxicity Criteria (version 3.0). Treatment tolerability was determined based upon whether or not the physician determined therapy was in the patient's best interest, whether the patient wanted to continue therapy or not, whether patients discontinued treatment due to progressive disease, or whether patients discontinued treatment due to toxicity.
Time frame: 12 Weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ATO + GO | Tolerability | Patients Who Completed 1 12-Week Cycle (C1) | 17 participants |
| ATO + GO | Tolerability | Patients Who Completed 2 12-Week Cycles (C2) | 7 participants |
| ATO + GO | Tolerability | Discontinue Tx During C1: Patient/Physician Choice | 5 participants |
| ATO + GO | Tolerability | Discontinue Tx During C1: Progressive Disease | 5 participants |
| ATO + GO | Tolerability | Discontinue Tx During C1:Treatment Toxicity | 3 participants |
| ATO + GO | Tolerability | Discontinue Tx After C1: Progressive Disease | 8 participants |
| ATO + GO | Tolerability | Discontinue Tx After C1: Treatment Toxicity | 2 participants |